Title: Xenobiotic Receptors in Mediating the Environmental Effects on Human Disease and Morbidity Project Summary/Abstract: This R35 proposal is designed to consolidate our current NIEHS funded projects into one program with the focus on understanding the role of xenobiotic receptors in regulating the metabolism of xenobiotics and endobiotics and the implications of this regulation in human health. The human population is at an increasing risk of developing chronic diseases, such as fibrosis, metabolic syndrome, alcoholic liver disease, and neurologic disorders. Environmental factors, including environmental chemicals, are among the major contributing factors in the pathogenesis of these chronic diseases. As such, understanding the mechanisms by which environmental chemicals modify human physiology and pathophysiology will help to design therapeutic or preventive strategies to mitigate the pathogenic effect of environmental chemicals. Xenobiotic receptors, including the xenobiotic nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and the PAS domain transcriptional factor aryl hydrocarbon receptor (AHR), are best known for their functions in sensing xenobiotic chemicals and regulating xenobiotic metabolism. Emerging evidence, mainly through the creation and characterization of gene knockout mice and identification of endogenous ligands, suggests that the xenobiotic receptors also have functions in regulating the homeostasis of endobiotics and impacting pathophysiology. Our overarching hypothesis is that xenobiotic receptors are critical environmental chemical-sensing transcriptional factors that mediate the environmental chemical effects on human disease and morbidity. Mechanistically, xenobiotic receptors impact the pathogenesis of human diseases by regulating the metabolism of xenobiotics and endobiotics in both the hepatic and extrahepatic tissues. We propose that the xenobiotic receptors are pivotal environmental modifiers that integrate signals from chemical exposures to the regulation of many aspects of human physiology. To test our hypothesis, we will assemble a highly experienced team and employ a broad spectrum of genetic and pharmacological tools, transdisciplinary approaches, and the expertise of an array of collaborators and clinician scientists to comprehensively define the roles that xenobiotic receptors play in environmentally influenced diseases, such as fibrosis, metabolic syndrome, alcoholic liver disease, and neurologic disorders. By understanding these pathways, we cannot only understand the environment-gene interactions and the implications of these interactions in human diseases, but also establish xenobiotic receptors and their target enzymes and transporters as potential therapeutic targets to manage these human diseases and morbidity. The insights gained from this R35 program can be used to design intervention strategies to manipulate these pathways via therapeutics or to guide human behavior or the human environment in a manner that is most beneficial to the sensitive populations. Over the next eight years, this R35 program will give us the freedom and power to make considerable advances in our understanding of xenobiotic receptors and how they influence human health. As the Principal Investigator, I am committed to devote 55% of my total effort to this R35 program, and all of my existing NIEHS funding will be consolidated into this grant if funded. I am confident that I can lead this R35 program, because I have studied xenobiotic receptors for two decades and have demonstrated a broad vision and made seminal contributions to our understanding of the toxicological and pathophysiological functions of xenobiotic receptors.